• Highlights
• Contents
• Indications and Usage
• Dosage and Administration
• Dosage Forms and Strengths
• Contraindications

• Warnings and Precautions
• Adverse Reactions
• Drug Interactions
• Use in Specific Populations
• Description

• Clinical Pharmacology
• Nonclinical Toxicology
• Clinical Studies
• References
• How Supplied/
  Storage and Handling

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of RECOTHROM have not been performed. The in vitro mutagenic potential of RECOTHROM has not been evaluated. In vitro cytotoxicity studies have been performed in mouse L929 fibroblast cell cultures and demonstrate a concentration dependent effect on cell morphology. The thrombin induced morphological changes were similar to those seen with bovine thrombin. The effect of RECOTHROM on fertility has not been characterized.

13.2 Animal Toxicology and/or Pharmacology

RECOTHROM was found to be well tolerated with minimal immunogenicity in nonhuman primates when applied directly to a liver wound with an absorbable gelatin sponge, USP.  RECOTHROM was also well tolerated and minimally immunogenic when administered subcutaneously once weekly for 4 weeks to nonhuman primates following repeat doses of 5405 units/m².  RECOTHROM was found to be non-irritating when instilled in the eyes (200 units) or applied to normal or abraded skin of rabbits (up to 1000 units/site).

13.3 Pharmacology

To evaluate RECOTHROM inhibition and clearance from the bloodstream, radiolabeled RECOTHROM was administered intravenously or subcutaneously to non-human primates and applied with an absorbable gelatin sponge, USP, in a rabbit hepatic wound model. RECOTHROM did not circulate in the blood as free, active molecule, but was rapidly inactivated (<5 minutes) after formation of complexes with endogenous inhibitors (e.g., antithrombin III); these complexes were cleared by the liver.
RECOTHROM applied with an absorbable gelatin sponge, USP, was shown to significantly decrease time to hemostasis (TTH) when compared to saline in a rabbit hepatic wound model and rat heminephrectomy model. RECOTHROM significantly reduced TTH when directly applied in a porcine partial-thickness excisional skin‑wound model as compared to saline control (or no treatment).
RECOTHROM applied with a gauze sponge decreased TTH in a concentration-dependent manner in both the rabbit and rat models. Concentrations of RECOTHROM > 1000 units/mL were no different than 1000 units/mL while the effect of RECOTHROM diluted to a concentration of 100 units/mL on TTH was indistinguishable from placebo.